Regulation of the MDR1 promoter by cyclic AMP-dependent protein kinase and transcription factor Sp1.
The expression of multidrug-resistance (MDR) in breast carcinoma cell line MCF-7/ADR50 is primarily dependent on the transcriptional activation of the MDR1 gene. We now report that MDR in this cell line is partially reversed by the type I cAMP-dependent protein kinase (PKA) inhibitor, 8-Cl-cAMP. MDR1 promoter activity was also regulated through a PKA-dependent pathway and was inhibited by 8-Cl-cAMP, and stimulated by the enantiomeric agonist, SpcAMP[S]. MDR1 promoter activity through an Sp1 response element was stimulated by exogenous Sp1, a factor that we have shown to be activated by PKA. These results indicate that MDR1 promoter activity is linked to the cAMP/PKA signaling pathway, and that PKA antagonists may be useful for reversing the multidrug-resistant phenotype.
Rohlff
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Department of Pharmacology and Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Glazer
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RI
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004317:Doxorubicin / Q000627:therapeutic use; D004330:Drosophila; D018432:Drug Resistance, Multiple; D019450:Genes, MDR / Q000187:drug effects*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D016329:Sp1 Transcription Factor / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016329:Sp1 Transcription Factor; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004317:Doxorubicin; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases